Respiratory failure is the major cause of mortality in spinal cord injury (SCI). Our lab has employed an animal model of SCI to demonstrate that a latent respiratory motor pathway can be activated to restore function to a hemidiaphragm paralyzed by an upper cervical (C2) spinal cord hemisection. This model is referred to as a C2 hemisection (HC2) and provides a relevant approach to assess potential therapies for respiratory impairment. Our studies with the model have led to the discovery that a drug-induced plasticity mediates sustained recovery long after cessation of drug treatment. As an extension of those previous studies, we now target two important molecular signaling pathways of plasticity for investigation (i) an initial cyclic AMP/PKA pathway and (ii) a subsequent PI3K/AKT and glycogen synthase kinase (GSK)-3b pathway. Our approach is innovative because we focus on activating two signaling pathways that converge on cyclic AMP Response Element Binding Protein (CREB)-mediated BDNF expression. A novel approach to restore respiratory function after C2 hemisection is the application of lithium to block GSK-3b and enhance BDNF levels. Electrophysiologic approaches combined with molecular/biochemical assays will be used to test two hypotheses: (1) that cyclic AMP/CREB-induced BDNF expression is the initial trigger (primo movens) for functional recovery in the HC2 model and (2) that inhibition of GSK-3b with lithium chloride, an antidepressant medication can induce functional recovery in the HC2 model via BDNF expression and feed-forward GSK-3b/CREB activation. The information to be derived from the proposed studies is vitally important to our further understanding of (1) how the spinal cord reacts to injury early at the molecular level, and (2) how we can target specific signaling pathways to improve recovery. Specifically, it is important in SCI to activate recovery processes early (so as to minimize secondary effects) and sustain maximal functional recovery. PUBLIC HEALTH RELEVANCE: Impaired respiratory function after spinal cord injury (SCI) regardless of the level of injury is the primary cause of morbidity and mortality in SCI. Our research on SCI using an animal model of upper cervical spinal cord injury (C2 hemisection) continues to provide insights towards improving respiratory function in afflicted individuals. It is anticipated that results from our research would further current understanding of how the spinal cord responds to injury and how we may be able to improve respiratory function after SCI in man.